This revised application for a Senior Scientist Award (K05) is submitted to enable the applicant to continue engaging in drug abuse research for the next five years. Research in the applicant's laboratory focuses on substituted amphetamine derivatives (MDMA, methamphetamine) and their propensity to selectively damage brain serotonin and/or dopamine neurons in animals and, possibly, humans. The long-term goals of this research are to better define risks and consequences of substituted amphetamine exposure in humans, and to further elucidate the role of serotonin and dopamine in the central nervous system (CNS), both in health and disease. In addition, this research seeks to identify the mechanism by which substituted amphetamines damage brain aminergic neurons, as this information may yield insight into the processes underlying neuronal loss in human neurodegenerative conditions. A variety of methods are used to achieve these goals. Studies in isolated systems (gene microarrays, synaptosomes and cultured cells) and intact animals (rodents) explore mechanisms of substituted amphetamine neurotoxicity, identify critical molecular requirements for the expression of neurotoxicity, and characterize the short- and long-term responses of serotonin and dopamine neurons to substituted amphetamine neurotoxicity. Studies in nonhuman primates seek to more accurately gauge the risk that substituted amphetamines pose to humans and to develop and validate methods for detecting the consequences of substituted amphetamine neurotoxicity in humans. Studies in humans, which include molecular PET imaging, pharmacologic challenges, neuropsychiatric evaluations, cognitive testing and polysomnographic evaluations, are designed to determine whether humans who use substituted amphetamines develop neurotoxicity and, if so, the functional consequences. By decreasing the amount of time required for clinical work, teaching, administration and other departmental duties, this K05 award will enable the applicant to optimize research productivity, continue training junior faculty and fellows in his laboratory, and participate in national and international forums intended to educate the public regarding the neurotoxic potential of substituted amphetamines.